Mood and anxiety disorders are the two most prevalent classes of mental disorder in the United States, affecting a significant number of individuals. In particular, Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) confer significant personal and societal costs; moreover, MDD and GAD are highly comorbid. Yet, we know surprisingly little about the unique and shared psychobiological underpinnings of these disorders and the mechanisms underlying their comorbidity. A growing body of research reveals that the constructs of stress and distress, and of arousal and regulation, are germane to our understanding of MDD and GAD. This is the first research, however, to examine these constructs in individuals with pure and co-occurring MDD and GAD within a single study. Specific objectives include: (1) investigating stress reactivity and regulation in individuals diagnosed with co-occurring and non-co-occurring MDD and GAD using a standardized laboratory stress paradigm; (2) examining stress processes in daily life in these same individuals; and (3) comparing laboratory-based assessment with experience sampling assessment of stress, reactivity, and regulation within and across these groups. To achieve these aims, all participants will undergo a baseline session that includes self-reports of symptom severity, stressors, affect, and affect regulation, followed by a counterbalanced experimental laboratory session and a one-week naturalistic experience sampling protocol. During the laboratory session, participants' neuroendocrine, autonomic, and subjective responses will be measured as they undergo a standardized stressor task used in the independent literatures on depression and anxiety. During the experience sampling period, participants' diurnal cortisol, reports of stressors, negative and positive affect, rumination, and worry will be measured in the context of their daily lives. An advanced, sophisticated set of statistical analyses will be conducted to test theoretically-driven hypotheses regarding group differences in mean levels and temporal variance on these measures, and simultaneously, key associations among these constructs in individuals within each group. Additional analyses will examine the stress, reactivity, and regulation measures with regard to their dimensional relations to depression and anxiety symptomatology. This research program will provide the applicant with training in new areas of knowledge and new methodologies, including the psychobiology of depression-anxiety interactions, the collection and interpretation of neuroendocrine and experience sampling data, the integration of endocrine and autonomic data, and hierarchical linear modeling techniques. This study addresses questions and issues surrounding MDD and GAD in a novel and integrated manner, and these findings will help to elucidate the nature of stress and reactivity, and the difficulties in reactivity and regulation associated with these emotional disorders. PUBLIC HEALTH RELEVANCE: Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) are highly prevalent, costly, and frequently comorbid psychiatric disorders. The results of this research will help to progress our understanding of the unique and shared psychobiological mechanisms underlying these disorders, to elucidate the nature of stress, reactivity, and regulation in co-occurring MDD and GAD, and to inform future studies integrating psychobiological constructs as measured in the laboratory with those arising naturalistically in daily life. These research findings, obtained and analyzed across multiple levels and domains, will also inform future intervention projects that will better target the diverse aspects of emotio dysregulation in these disorders.